Seasonal influenza A is a major public health problem, killing more than 250,000 worldwide each year, while creating an economic burden for millions. Pandemic influenza, which occurs when a new virus emerges and infects people globally that have little or no immunity, represents even a greater threat to human health; for example, the 1918 “Spanish Flu” pandemic caused an estimated 50 million deaths. Of continuing concern is highly pathogenic avian influenza (HPAI) which has demonstrated mortality rates of greater than 50% in infected humans. H5 as well as H7 influenza viruses are endemic in poultry in certain parts of the world. These viruses currently do not appear to be able to transmit readily from person to person, but recent data for avian H5 indicate that only a few amino acid changes are sufficient to enable this virus to spread through aerosol transmission in a mammalian in vivo model system.
Antibodies capable of broadly neutralizing influenza A and/or B viruses have recently been described, such as CR9114 (as disclosed in WO2013/007770), CR6261 (disclosed in WO2008/028946), FI6 (described in Corti et al., Science 333, 850-856 (2011)). These antibodies have been shown to interact with a large variety of hemagglutinin proteins and to neutralize a broad spectrum of influenza strains. As a result of their potency and breadth, such antibodies are now being developed for therapeutic treatment of severely ill patients and prophylactic applications for people belonging to high risk groups. The relative high costs of goods and their parenteral administration, however, are expected to limit the use of monoclonal antibodies in larger populations.
Other currently available agents to prevent and/or treat influenza infection are also associated with severe limitations. Anti-viral drugs such as the neuraminidase inhibitors oseltamivir and zanamivir and the M2 inhibitors amantadine and rimantadine have limited efficacy if administered late in infection and widespread use is likely to result in the emergence of resistant viral strains. Furthermore the use of oseltamivir in adults is associated with adverse effects, such as nausea, vomiting, psychiatric effects and renal events.
Furthermore, the efficacy of influenza vaccines has been shown to be suboptimal for high-risk patients (elderly) and the permanent antigenic changes of the circulating influenza viruses requires annual adaptation of the influenza vaccine formulation to ensure the closest possible match between the influenza vaccine strains and the circulating influenza strains.
The discovery of novel influenza antivirals acting on hemagglutinin (HA) as an alternative strategy to prevent and/or treat influenza infection is also hampered by the large sequence variability of this protein. Hemagglutinin ligands described so far therefore only show activity against a limited number of closely related influenza strains.
In view of the severity of respiratory illness caused by influenza A viruses, as well has the high economic impact of the seasonal epidemics, and the continuing risk for pandemics, there is an ongoing need for new effective inhibitors with broad activity against influenza A viruses and which can be used as medicaments for prevention or treatment of influenza infection.